JPH069460A - Production of di-(protected 2,3-hydroxymethyl)cyclobutanol - Google Patents

Abstract

PURPOSE: To prepare diprotected 2,3-hydroxymethyl cyclobutanol useful as an intermediate in the preparation of antimicrobial agents by reacting a specified protected cyclobutanone with a reducing agent.

CONSTITUTION: A compd. represented by formula I [where Prot is hydroxy- protecting group, which is a hindered silyl, (substd.)benzyl or -C(=)R₁ (R₁ is a 1-6C alkyl or phenyl)] is treated with a reducing agent selected from the group of i) dialkylaluminum chloride, ii) alkylaluminum dichloride, iii) trialkylaluminum (wherein Prot is a group except the group represented by formula II), iv) hydrogen in the presence of ruthenium black or ruthenium/ alumina catalyst, v) diphenylsilane in the presence of tris(triphenylphosphine) rhodium (I) chloride and vi) iridium tetrachloride in the presence of phosphorous acid, to obtain the objective compd. represented by formula III, e.g. [1 S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol.dibenzyl ether.

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing diprotected 2,3-hydroxymethylcyclobutanol, and more particularly, an intermediate for producing an antibacterial agent, which comprises reacting a specific protected cyclobutanone with a reducing agent. The present invention relates to an improved process for producing a cyclobutanol compound useful as

[0002]

The manufacturing method according to the present invention has the formula:

[Chemical 5] (Wherein Prot is a protecting group) di-protected 2,3
A process for the preparation of hydroxymethylcyclobutanol (I), which has the formula:

[Chemical 6] Of cyclobutanone compound (II) of diphenylaluminum chloride, alkylaluminum dichloride, trialkylaluminum compound, hydrogen in the presence of ruthenium black or ruthenium / alumina catalyst, diphenyl in the presence of tris (triphenylphosphine) rhodium (I) chloride. By treatment with a reducing agent selected from the group of iridium tetrachloride in the presence of silane and phosphorous acid, the undesired formula:

[Chemical 7] To obtain the desired cyclobutanol compound of formula (I) in preference to the isomeric compound of

In the production method of the present invention, the cyclobutanone compound (II) can be used in its optically active (2S-trans) form (hereinafter also referred to as [2S, 3S]). In this case, the desired cyclobutanol compound (I)
Is also optically active, that is, [1S- (1α, 2β, 3
β)]. This optically active cyclobutanol compound (I) is an optically active antibacterial agent such as [1R- (1α,
2β, 3α)]-2-Amino-9- [2,3-bis (hydroxymethyl) cyclobutyl] -1,9-dihydro-
It can be converted to 6H-purin-6-one.

In the production method of the present invention, the cyclobutanone compound (II) can be used as a racemic compound, in which case the desired cyclobutanol compound (I) is optically active, that is, (1α, 2β, 3β). Becomes This racemic cyclobutanol compound (I) is a racemic antibacterial agent such as (±)-(1α, 2β, 3α)-
2-amino-9- [2,3-bis (hydroxymethyl)
Cyclobutyl] -1,9-dihydro-6H-purine-6
-Can be turned on.

According to the relative stereochemistry of the substituents on the cyclobutyl ring in the diprotected 2,3-hydroxymethylcyclobutanol of formula (I), the hydroxy substituents are replaced by adjacent --CH ₂ --O--Prot substitutions. In the cis position relative to the base,
The two -CH ₂ -O-Prot substituents are shown that in the trans position to one another.

The above cyclobutanone compound (II) is converted into a dialkylaluminum chloride (for example, diisobutylaluminum chloride), an alkylaluminum dichloride (for example, isobutylaluminum dichloride),
A trialkylaluminum compound (eg triisobutylaluminum), hydrogen in the presence of ruthenium black or a ruthenium / alumina catalyst, diphenylsilane in the presence of tris (triphenylphosphine) rhodium (I) chloride, and phosphorous acid. By treatment with a reducing agent selected from the group of iridium tetrachloride, the desired di-protected 2,3-hydroxymethylcyclobutanol of formula (I) is obtained in preference to the undesired isomeric compound (III). can get.

"Alkyl" has 1 to 2 carbon atoms.
0, preferably 3 to 10 straight or branched chain groups are designated.

Prot is a hydroxy protecting group. Suitable protecting groups include hindered silyl groups such as t-butyldimethylsilyl, t-butyldiphenylsilyl,
(Triphenylmethyl) dimethylsilyl, methyldiisopropylsilyl and triisopropylsilyl. Also suitable as protecting groups are benzyl and substituted benzyl groups such as p-methoxybenzyl and the formula:

[Chemical 8] (Wherein R ₁ is a linear or branched lower alkyl having 1 to 6 carbon atoms or phenyl), and an acyl group can also be mentioned.
A preferred acyl protecting group is benzoyl where R ₁ is phenyl.

When the reducing agent used in the production method of the present invention is dialkylaluminum chloride, suitable reaction solvents include non-reactive neutral solvents such as methylene chloride and toluene. The reaction can be carried out at a temperature of about -90 ° C to solvent boiling point, preferably about -90 to 0 ° C, most preferably about -40 ° C.

When the reducing agent used in the production method of the present invention is an alkylaluminum dichloride (eg, isobutylaluminum dichloride) or a trialkylaluminum compound (eg, triisobutylaluminum), suitable reaction solvents include methylene chloride and toluene. A neutral solvent that does not react can be used. The reaction is about −
It can be carried out at a temperature of 90 ° C to the boiling point of the solvent, preferably about -90 to 0 ° C. If the reducing agent used is a trialkylaluminium compound, the protecting group Prot must not be benzoyl.

When the reducing agent used in the production method of the present invention is iridium tetrachloride in the presence of phosphorous acid, suitable reaction solvents include water, methanol, propanol,
Mention may be made of hydroxylic solvents such as isopropanol or the like or mixtures thereof (eg water / isopropanol). The reaction is about 50-100 ° C, most preferably about 8
It can be carried out at a temperature of 0 ° C.

When the reducing agent used in the process of the present invention is hydrogen in the presence of a ruthenium black catalyst, suitable reaction solvents include hydroxyl solvents (preferably methanol) such as methanol, isopropanol or mixtures thereof. To be

When the reducing agent used in the process of the present invention is hydrogen in the presence of a ruthenium / alumina catalyst, suitable reaction solvents include hydroxyl solvents such as methanol (which is preferred), ethanol, etc. , Except for isopropanol). The reaction is about -90 ° C
Solvent boiling point, preferably 0-50 ° C, most preferably about 2
It can be carried out at a temperature of 5 ° C.

When the reducing agent used in the production method of the present invention is diphenylsilane in the presence of tris (triphenylphosphine) rhodium (I) chloride, suitable reaction solvents include benzene, toluene, hexane, cyclohexane and the like ( Preferred is toluene), or alternatively, the reaction can be carried out in the absence of a solvent.
When the reaction is carried out in the presence of a solvent, the reaction is carried out at a temperature of about 0 ° C to the boiling point of the solvent, preferably about 25 ° C. When the reaction is carried out without a solvent, the reaction is carried out at a temperature of about 0 to 120 ° C.

In the preferred process of the present invention, the reducing agent is a dialkylaluminum chloride, most preferably diisobutylaluminum chloride, the protecting group Prot is benzoyl, and the starting cyclobutanone compound (I
I) is an optically active (2S-trans) form.

Optical activity of formula (II) (2S-trans)
Di-protected 2,3-hydroxymethylcyclobutanone is commercially available from Bisatch et al., US Patent No. 5064961, Norbeck et al., European Patent Application No. 366059, Ichikawa et al., European Patent Application No. 358154, and Pariza et al. .452729, or Amadd European Patent Application No. 4588634. The racemic (trans) -diprotected 2,3-hydroxymethylcyclobutanone of formula (II) is prepared according to the European patent application No. 335355 of Slusarchyk et al. And the European patent application of Norbeck et al. And Ichikawa et al. It can be manufactured. Another method for producing the optically active cyclobutanone compound (II) is described in God Frey et al., US Pat. No. 5,185,463.

US Pat. No. 50649 of Bisatch et al.
61, the optically active [1S- (1
α, 2β, 3β)] diprotected 2,3-hydroxymethylcyclobutanol by treatment with tosyl chloride,
formula:

[Chemical 9] The cyclobutane compound (IV) can be obtained.

Then the cyclobutane compound (IV)
formula:

[Chemical 10] Treated with benzyloxyguanidine (V) of formula:

[Chemical 11] Compound (VI) of

By removing the protecting group of compound (VI), an antibacterial agent [1R- (1α, 2β, 3α)]-
2-amino-9- [2,3-bis (hydroxymethyl)
Cyclobutyl] -1,9-dihydro-6H-purine-6
-Get on.

[0020]

EXAMPLES The following examples are specific examples of the production method of the present invention. Example 1 [1S- (1α, 2β, 3β)]-3-hydroxy-
Preparation of 1,2-cyclobutane dimethanol dibenzoate ester: -Charge 2385 ml anhydrous methylene chloride into a 3 liter 3-necked flask equipped with mechanical stirrer, internal digital thermometer, dropping funnel and nitrogen inlet. To do. After cooling to -40 ° C, diisobutylaluminum chloride (156.6 g, 886 mmol, 1.27 molar equivalents) is added. Add methylene chloride (600 m) to this cold solution.
(2S-trans) -2,3-bis [(benzoyloxy) methyl] cyclobutanone in l) (235 g, 69
9 mmol) solution is added dropwise with a dropping funnel over 63 minutes. The reaction is maintained at -40 ° C for an additional 70 minutes.
Quench the reaction by slowly adding methanol (502 ml). While suppressing the reaction, the temperature is over 1 hour,
The temperature rises from about -40 ° C to -32 ° C. Remove the cooling bath and add saturated aqueous ammonium chloride solution (502 ml). After stirring for 18 hours, the mixture is filtered over anhydrous magnesium sulfate (502 g) and the filter cake is washed thoroughly with methylene chloride. The filtrate is concentrated under reduced pressure and the residue is pumped under suction 35
Dry at ℃ to obtain 287.3g of crude product. The slightly damp solid was crystallized from about 2 liters of methanol and about 400 ml of water to give 160.6 g (68% yield) of [1S
-(1α, 2β, 3β)]-3-Hydroxy-1,2-
Cyclobutane dimethanol dibenzoate ester is obtained. mp 75-77 ° C, TLC (silica gel, 40
% Ethyl acetate / hexane), Rf = 0.39, [α] _D =
-15.3 ° (C = 1.1, chloroform), HPLC:
HI (215 nm, Zorabax-cyano column, water / acetonitrile gradient) 99.5%. Elemental analysis (C ₂₀ H ₂₀ O ₅₎ Calculated value: C 70.38, H 5.94, H 2 O 0.27 Found: C 69.92, H 5.87, H 2 O 0.27

Example 2 [1S- (1α, 2β, 3β)]-3-Hydroxy-
Preparation of 1,2-cyclobutanedimethanol dibenzyl ether: 0.7 of isobutylaluminum chloride
To a 1M hexane solution (3.41 ml, 2.42 mmol) at -78 ° C (2S-trans) -2,3-bis [(benzyloxy) methyl] cyclobutanone (0.5 g, in toluene (1 ml). 1.61 mmol) is added dropwise.
The mixture is allowed to warm slowly to room temperature over 2 hours. After stirring for 30 minutes at room temperature, the mixture is left at 0 ° C. overnight. After diluting with ethyl acetate, 10% hydrochloric acid is added to the reaction mixture to quench the reaction. The organic phase is washed with brine, dried (magnesium sulphate), solvent evaporated and [1S- (1α, 2
β, 3β)]-3-Hydroxy-1,2-cyclobutanedimethanol dibenzyl ether is obtained. TLC (5
0% ethyl acetate / hexane), Rf = 0.53.

Example 3 [1S- (1α, 2β, 3β)]-3-hydroxy-
Preparation of 1,2-cyclobutane dimethanol dibenzyl ether: -triisobutylaluminum (0.91M solution in hexane, 0.9 ml, 0.9 ml) in toluene (2 ml).
816 mmol) in toluene (4
(2S-trans) -2,3-bis [(benzyloxy) methyl] cyclobutanone (0.2 g, 0.6) in
45 mmol) solution is added dropwise over 10 minutes. The mixture is stirred at −50 ° C. for 4 hours and −40 ° C. for 1 hour. To the reaction mixture was added triisobutylaluminum solution (1 ml, 0.91 mmol). After stirring for 30 minutes, 10% hydrochloric acid (2 ml) was added at -40 ° C to quench the reaction. The organic phase is washed with brine, dried (magnesium sulphate), solvent evaporated and [1S- (1α, 2β, 3
β)]-3-Hydroxy-1,2-cyclobutanedimethanol dibenzyl ether is obtained. TLC (30% ethyl acetate / hexane), Rf = 0.3. Product is about 5%
It contains an isomer compound. TLC (30% ethyl acetate / hexane), Rf = 0.2.

Example 4 [1S- (1α, 2β, 3β)]-3-Hydroxy-
Preparation of 1,2-cyclobutane dimethanol dibenzyl ether: (2S- in isopropanol (3 ml)
Trans) -2,3-bis [(benzyloxy) methyl] cyclobutanone (0.25 g, 0.806 mmol), iridium tetrachloride (0.016 g, 0.0).
A mixture of 483 mmol), phosphorous acid (0.397 g, 4.84 mmol) and water (0.3 ml) is refluxed overnight. The solvent is evaporated on a rotary evaporator. The residue is dissolved in ethyl acetate and washed successively with 10% hydrochloric acid, brine and 5% sodium bicarbonate. The organic layer was dried (magnesium sulfate) and the solvent was evaporated to [1S- (1α, 2β, 3
β)]-3-Hydroxy-1,2-cyclobutanedimethanol dibenzyl ether is obtained. TLC (40% ethyl acetate / hexane), Rf = 0.51.

Example 5 Preparation of (1α, 2β, 3β) -3-hydroxy-1,2-cyclobutanedimethanol dibenzoate ester: -A suspension of ruthenium black (20 mg) in isopropanol (1 ml), Preliminarily hydrogenate for 1 hour at room temperature under hydrogen at 1 atmosphere. To this mixture was added (trans) -2,3-bis [(benzoyloxy) methyl] cyclobutanone (200 m) in isopropanol (11 ml).
g) is added and the combined mixture is stirred at room temperature under 1 atm of hydrogen. After 21 hours, by HPLC (1α,
2β, 3β) -3-Hydroxy-1,2-cyclobutanedimethanol dibenzoate ester and the isomeric compound (1α, 2β, 3α) -3-hydroxy-1,2-
It is noted that the cyclobutane dimethanol dibenzoate ester is present in a ratio of 84:16.

Example 6 Preparation of (1α, 2β, 3β) -3-hydroxy-1,2-cyclobutanedimethanol dibenzoate ester: (trans) -2,3 in methanol (2 ml)
-Bis [(benzoyloxy) methyl] cyclobutanone (50 mg) and 5% ruthenium / alumina (10 m
The mixture of g) is stirred at room temperature under 1 atm of hydrogen. 46
After hours, by HPLC, (1α, 2β, 3β) -3-
Hydroxy-1,2-cyclobutane dimethanol dibenzoate ester and isomer compounds (1α, 2β,
It is noted that the 3α) -3-hydroxy-1,2-cyclobutanedimethanol dibenzoate ester is present in the ratio 73:27.

Example 7 Preparation of (1α, 2β, 3β) -3-hydroxy-1,2-cyclobutanedimethanol dibenzoate ester: (trans) -2, in toluene (0.75 ml)
3-bis [(benzoyloxy) methyl] cyclobutanone (50 mg, 0.148 mmol) and tris-
To a stirred solution of (triphenylphosphine) -rhodium (I) chloride (1.4 mg, 0.0015 mmol) was added diphenylsilane (27.4 μl, 0.148 millimoly) and kept at room temperature for 15 minutes under argon atmosphere. To do. The reaction mixture was then concentrated to an oil which contained a catalytic amount of p-
Stir for 1 hour at room temperature with 10% aqueous methanol containing toluene sulfonic acid (1 ml). The mixture is concentrated to an oil which is partitioned between water and ethyl acetate. The ethyl acetate layer is washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and the solvent removed to give 55 mg of a clear oil. H of this oil
By PLC, (1α, 2β, 3β) -3-hydroxy-1,2-cyclobutanedimethanol dibenzoate ester and the isomer compound (1α, 2β, 3α) -3
It is noted that the -hydroxy-1,2-cyclobutane dimethanol dibenzoate ester is present in the ratio 82:18.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Gregory S. Visatch, Taylor Court 12133, Lawrenceville, NJ, USA (72) Inventor Richard H. Muller 66, Lindberg Road, Lingoles, NJ, USA

Claims (10)

[Claims] 1. The formula: (In the formula, the hydroxy substituent is the adjacent -CH ₂ -O-Prot.
It is in the cis position with respect to the substituent and has two --CH ₂ --O--
The Prot substituents are in the trans position relative to each other) for the preparation of compounds of formula: In the presence of dialkylaluminium chloride, alkylaluminum dichloride, trialkylaluminum compound, ruthenium black or ruthenium / alumina catalyst, diphenylsilane in the presence of tris (triphenylphosphine) rhodium (I) chloride, and Treated with a reducing agent selected from the group of iridium tetrachloride in the presence of phosphoric acid, where alkyl is a straight or branched chain group having 1 to 20 carbon atoms, Prot is a hindered silyl group, benzyl, substituted benzyl. Or [Chemical 3] , R ₁ is a linear or branched lower alkyl having 1 to 6 carbon atoms or phenyl, provided that when the reducing agent is a trialkylaluminum compound, Prot is A manufacturing method characterized by not being. 2. The reducing agent is a dialkylaluminum chloride, and the alkyl is a straight or branched chain group having 3 to 10 carbon atoms,
And Prot is a hindered silyl selected from the group of t-butyldimethylsilyl, t-butyldiphenylsilyl, (triphenylmethyl) dimethylsilyl, methyldiisopropylsilyl and triisopropylsilyl, or Prot is benzyl, p-methoxybenzyl or benzoyl. The manufacturing method according to claim 1, wherein 3. The reaction is carried out at a temperature of about −90 ° C. to the boiling point of the solvent in the presence of a reducing agent of diisobutylaluminum chloride and Prot of benzoyl in the presence of a neutral solvent selected from the group of methylene chloride and toluene. The manufacturing method according to 2. 4. The reducing agent is alkylaluminum dichloride, and the alkyl is a linear or branched chain group having 3 to 10 carbon atoms,
And Prot is a hindered silyl selected from the group of t-butyldimethylsilyl, t-butyldiphenylsilyl, (triphenylmethyl) dimethylsilyl, methyldiisopropylsilyl and triisopropylsilyl, or Prot is benzyl, p-methoxybenzyl or benzoyl. The manufacturing method according to claim 1, wherein 5. The reaction according to claim 4, wherein the reducing agent is isobutylaluminum dichloride, and the reaction is carried out in the presence of a neutral solvent selected from the group of methylene chloride and toluene at a temperature of about −90 ° C. to the boiling point of the solvent. Manufacturing method. 6. The reducing agent is a trialkylaluminum compound, and the alkyl is a linear or branched group having 3 to 10 carbon atoms,
And Prot is a hindered silyl selected from the group of t-butyldimethylsilyl, t-butyldiphenylsilyl, (triphenylmethyl) dimethylsilyl, methyldiisopropylsilyl and triisopropylsilyl, or Prot is benzyl or p-methoxybenzyl. The manufacturing method according to claim 1. 7. The method according to claim 6, wherein the reducing agent is triisobutylaluminum, and the reaction is carried out in the presence of a neutral solvent selected from the group of methylene chloride and toluene at a temperature of about −90 ° C. to the boiling point of the solvent. Manufacturing method. 8. The reducing agent is hydrogen in the presence of ruthenium black, and Prot is t-butyldimethylsilyl, t-.
Hindered silyl selected from the group of butyldiphenylsilyl, (triphenylmethyl) dimethylsilyl, methyldiisopropylsilyl and triisopropylsilyl,
Or Prot is benzyl, p-methoxybenzyl or benzoyl, in a solvent selected from the group of methanol, isopropanol and mixtures thereof, about -9
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent; or the reducing agent is hydrogen in the presence of ruthenium / aluminum, and Pro.
t is hindered silyl selected from the group of t-butyldimethylsilyl, t-butyldiphenylsilyl, (triphenylmethyl) dimethylsilyl, methyldiisopropylsilyl and triisopropylsilyl, or Prot is benzoyl and The process according to claim 1, wherein the reaction is carried out in a solvent selected from the group at a temperature of about -90 ° C to the boiling point of the solvent. 9. The reducing agent is diphenylsilane in the presence of tris (triphenylphosphine) rhodium (I) chloride, and Prot is t-butyldimethylsilyl, t-butyldiphenylsilyl, (triphenylmethyl) dimethylsilyl, methyl. A hindered silyl selected from the group of diisopropylsilyl and triisopropylsilyl, or Prot is benzyl, p-methoxybenzyl or benzoyl in a solvent selected from the group of benzene, toluene, hexane and cyclohexane at about 0 ° C to
The reaction is carried out at the temperature of the boiling point of the solvent, or in the absence of the solvent,
The method according to claim 1, wherein the reaction is carried out at a temperature of about 0 to 120 ° C. 10. The reducing agent is iridium tetrachloride in the presence of phosphorous acid, and Prot is t-butyldimethylsilyl, t-butyldiphenylsilyl, (triphenylmethyl) dimethylsilyl, methyldiisopropylsilyl and triisopropylsilyl. Hindered silyl selected from the group, or Prot is benzyl, p-methoxybenzyl or benzoyl, water, methanol,
The process according to claim 1, wherein the reaction is carried out at a temperature of about 50 to 100 ° C. in the presence of a solvent selected from the group consisting of propanol, isopropanol and a mixture thereof.